The experiments described in this proposal are focused on understanding the mechanisms underlying the maintenance of stable heritable states of gene expression during development, as well as their developmentally programmed reversal. The Drosophila homeotic genes remain a preeminent source of new insights into these mechanisms. We focus on the Polycomb Group (PcG) and Trithorax Group (TrxG) proteins, which regulate chromatin states associated respectively with transcriptionally silent and active states through their chromatin modifying and remodeling enzyme activities. Their activities are now implicated in many biological processes, including genome-wide control of transcriptional programs, stem cell maintenance and differentiation, regeneration, longevity and others. Disturbances in the function or regulation of PcG and TrxG proteins are now known suspected to underlie a wide variety of disease states from cancer, chronic inflammation, obesity, diabetes, metabolic syndrome and others, some of which appear to manifest heritable transgenerational effects. The aims of proposed work are: 1) to further investigate a newly discovered activity of the TRX protein that will shed new light on its function in a maintaining active states and antagonizing Polycomb silencing; 2) to investigate a new activity of the CBP protein which functionally integrates it even more intimately with TRX and suggests a mechanism by which TRX affects H3K27 acetylation by CBP to antagonize Polycomb silencing; 3) to investigate a newly discovered role of the Polycomb protein (PC) in negatively modulating / antagonizing maintenance of active chromatin states. Understanding the role of these new factors in regulating Polycomb silencing will provide new insights into the mechanisms underlying the epigenetic inheritance of stable chromatin states during development.